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REVIEW
New Perspectives for Mucolytic, Anti-inflammatory
and Adjunctive Therapy with 1,8-Cineole in COPD
and Asthma: Review on the New Therapeutic
Approach
Lisa Joy Juergens .Heinrich Worth .Uwe R. Juergens
Received: January 8, 2020
ÓThe Author(s) 2020
ABSTRACT
The mucolytic monoterpene 1,8-cineole (euca-
lyptol), the major constituent of eucalyptus
species, is well known for its anti-inflammatory,
antioxidant, bronchodilatory, antiviral and
antimicrobial effects. The main protective
antiviral, anti-inflammatory and mucolytic
mechanisms of 1,8-cineole are the induction of
interferon regulatory factor 3 (IRF3), the control
of nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-jB) along with decreasing
mucin genes (MUC2,MUC19). In normal
human monocytes direct inhibition was shown
of reactive oxygen species (ROS)-mediated
mucus hypersecretion and of steroid resistence
inducing superoxides (O
2
-
) and pro-inflamma-
tory hydrogen peroxides (H
2
O
2
) with partial
control of superoxide dismutase (SOD), which
enzymatically metabolizes O
2
-
into H
2
O
2
.By
inhibition of NF-jB, 1,8-cineole, at relevant
plasma concentrations (1.5 lg/ml), strongly and
significantly inhibited in normal human
monocyte lipopolysaccharide (LPS)-stimulated
cytokines relevant for exacerbation (tumour
necrosis factor alpha (TNFa), interleukin (IL)-1b
and systemic inflammation (IL-6, IL-8). Infec-
tious agents and environmental noxa have
access via TNFaand IL-1bto the immune sys-
tem with induction of bronchitis complaints
and exacerbations of chronic obstructive pul-
monary disease (COPD), asthma and asthma–-
COPD overlap. In lymphocytes from healthy
human donors 1,8-cineole inhibited TNFa, IL-
1b, IL-4 and IL-5 and demonstrated for the first
time control of Th1/2-type inflammation. 1,8-
Cineole at relevant plasma levels increased
additively in vitro the efficacy of inhaled
guideline medications of budesonide (BUD) and
budesonide ?formoterol ,and preliminary data
also showed increased efficacy of long-acting
muscarinic receptor antagonist (LAMA)-medi-
ated cytokine inhibition in vitro. On the basis of
the preclinical data, earlier randomised con-
trolled studies with adjunctive therapy of 1,8-
cineole (3 9200 mg/day) for 6 months showed
improvement of uncontrolled asthma by sig-
nificant improvement of lung function, noc-
turnal asthma and quality of life scores and in
COPD decrease of exacerbations (-38.5%)
(during wintertime). This review reports an
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U. R. Juergens (&)
Department of Pulmonary Rehabilitation, Asklepios
Nordseeklinik Westerland, Norderstraße 81, 25980
Sylt, Germany
e-mail: Uw.Juergens@asklepios.com;
juergens_uwe@t-online.de
L. J. Juergens
Medical University of Tu
¨bingen, Medical School,
72070 Tu
¨bingen, Germany
e-mail: lisa.joy@juergensfamily.de
H. Worth
Specialist Forum Fu
¨rth, 90762 Fu
¨rth, Germany
Adv Ther
https://doi.org/10.1007/s12325-020-01279-0
update with reference to the literature of 1,8-
cineole, also as adjunctive therapy, as a thera-
peutic agent for the protection and control of
inflammatory airway diseases.
Keywords: Asthma; Chronic obstructive
pulmonary disease (COPD); Mucolytics;
Sinusitis; 1,8-Cineole
Key Summary Points
This new review focuses on the current
status of the monoterpene 1,8-cineole to
suggest therapy and adjunctive therapy
with 1,8-cineole for inflammatory airway
diseases.
It is the first review of the current status of
the known pathogenetic mechanisms of
inflammatory airway diseases to discuss,
in comparison to current guideline
recommendations for asthma and COPD,
the underlying mechanisms of action and
clinical benefits of recommended
medications compared to 1,8-cineole
alone and as adjunctive therapy for the
treatment of COPD, asthma and sinusitis.
Therefore, this is the first review to report
on the potential advances in therapy with
1,8-cineole.
INTRODUCTION
The monoterpene 1,8-cineole (eucalyptol) is
chemically a terpenoid oxide thatis well known as
the major constituent (77–84%) of various euca-
lyptus species and also the component of other
essential oils with a relevant meaning for clinical
effect. Eucalyptus oil is well known for its biolog-
ical activities, including anti-inflammatory,
antioxidant, free radical scavenging, mucolytic/
secretolytic, bronchodilatory, antiviral and
antimicrobial effects, as reviewed elsewhere [1].
These effects will be of relevance for the treatment
of airway diseases in addition to having antifun-
gal, antiseptic, antispasmodic, analgetic and
antitumour properties. Essential oils may vary in
their plant concentrations depending on various
regional influences, such as agroclimatic condi-
tions [2]; however, 1,8-cineole can be made
available in a standardized form for clinical use
following extraction from eucalyptus oil.
A further review evaluated the potential
biological effects of 1,8-cineole on the most
promising targets in the treatment of chronic
obstructive pulmonary disease (COPD) in ani-
mal experimental models [3]. In this report, 1,8-
cineole interacted with relevant mediators of
pathophysiological pathways of COPD and
identified receivers and membrane channels,
oxidative stress, transcription molecules and
expression of cytokines, cell adhesion mole-
cules and neutrophil chemotaxis, pro-inflam-
matory cells, proteases and remodelling as
potential therapeutic targets. The authors con-
cluded from these findings that eucalyptol (1,8-
cineole) showed a relevant additional treatment
option to the use of anti-inflammatory drugs in
asthma and COPD.
Former and current conventional treatments
have long been geared toward relieving symp-
toms, preventing recurrent exacerbations, pre-
serving optimal lung function and enhancing
the overall quality of life [4]. Because asthma
and COPD are chronic inflammatory diseases, it
is essential to determine whether new approa-
ches with anti-inflammatory and antioxidant
agents can halt or slow the decline in lung
function that occurs in response to the disease
when selecting candidate drugs. In this regard,
the consensus of a group of Chinese pulmonary
physicians [5] and a collaborative task force
between the European Respiratory Society and
the American Thoracic Society (ERS/ATS guide-
lines) [6] was focused on the prevention of
excerbations in COPD by mucolytics, macro-
lides, long-acting muscarinic receptor antago-
nists (LAMAs)/long-acting b
2
-agonists (LABAs)
in stable COPD and the phosphodiesterase
(PDE)-IV inhibitor roflumilast in COPD with
associated bronchitis. Selected thresholds by the
task force for clinically important differences
included relative risk reductions of mortality
(15%), exacerbations (20%), adverse events
Adv Ther
(15%) and a four-point reduction on the
St. George’s Respiratory Questionnaire (SGRQ)
with complete medications for COPD to deter-
mine the add-on effect. A review and six ran-
domized studies of at least 1 year with N-
acetylcysteine (NAC), carbocysteine and
ambroxol in patients with COPD (forced expi-
ratory volume in 1 s (FEV1) 30–79%), with at
least two exacerbations per year during the
previous 2 years, were evaluated. Hospitaliza-
tions and COPD exacerbations were reduced
(rate ratio 0.79) with a stronger effect of high-
dose (e.g. NAC 600 mg twice daily) mucolytic
therapy (rate ratio 0.69, 95% CI 0.50–0.94),
compared to low-dose mucolytic therapy with
no significant reduction (rate ratio 0.87, 95% CI
0.66–1.14) and no increase of adverse effects.
This article is based on previously conducted
studies and does not contain any studies with
human participants or animals performed by
any of the authors. It is the first review to report
on the current knowledge of the known muco-
lytic agent 1,8-cineole (eucalyptol) with regard
to its anti-inflammatory, antioxidant and
antimicrobial activities for the treatment of
inflammatory airway diseases. In particular, the
importance of 1,8-cineole as adjunctive therapy
to control systemic inflammation and to inter-
act with guideline medications for COPD and
asthma by its exhaled availability via the
peripheral airways will be discussed.
APPROVED EFFICACY OF 1,8-
CINEOLE IN RANDOMIZED,
PLACEBO-CONTROLLED TRIALS
Chronic rhinosinusitis is a well-known risk
factor (hazard ratio 3.7) for 30-day readmission
due to frequent exacerbations of asthma and
COPD and outpatient management of the
upper and lower airways is recommended [7,8].
The highest odds ratios (OR) for exacerbated
asthma were reported for symptoms of chronic
bronchitis (2.70) and sinusitis (1.5) besides
other comorbidities. In perennial allergic
rhinitis with seasonal exacerbations (PARSE
study), symptoms of rhinitis were reportedly
worse in difficult-to-control vs. easy-to-control
asthma, and seasonal patterns also partially
corresponded to those of difficult-to-control
asthma [9]. The first placebo-controlled study
with 1,8-cineole (two 100 mg capsules three
times daily for 7 days) in acute non-purulent
sinusitis showed significant reduction of the
mean symptoms sum-score after 4 and 7 days
and amelioration of headache of secondary end
points [10]. The effect of 1,8-cineole on con-
trolling mucus hypersecretion was studied in a
model of experimental rhinosinusitis on
lipopolysaccharide (LPS)-stimulated nasal slice
cultures ex vivo and showed for the first time
significant decrease in the number of mucin-
filled goblet cells with reduction of the mucin
genes MUC2 and MUC19 in association with
significantly attenuated nuclear factor kappa-
light-chain-enhancer of activated B cells (NF-
jB) activity [11]. Since the common cold is
known as the most frequent reason for virus-
exacerbated upper and lower inflammatory air-
way diseases, such as acute and chronic rhi-
nosinusitis in the context of frequent
exacerbations of COPD and asthma, the same
group also found that 1,8-cineole induced
activity of the antiviral transcription factor
interferon regulatory factor 3 (IRF3) in the
presence of its inhibitory effect on pro-inflam-
matory NF-jB signalling [12].
At this stage of our knowledge, seasonal or
permanent daily adjunctive therapy with 1,8-
cineole for the protection of exacerbated airway
disease of the upper and lower airways is to be
recommended, especially in the presence of
increased risks of sinusitis with existing asthma,
asthma–COPD overlap and COPD.
In the first preliminary placebo-controlled
study in severe steroid-dependent asthma (n=
32), following a run-in phase of 2 months to
determine the minimal effective dose of daily
prednisolone, patients were randomly allocated
to receive either 1,8-cineole (3 9200 mg/day)
(Soledum
Ò
forte capsules, registered in various
European countries, also available as Soledum
addicur capsules registered in Germany since
1 November 2019), or placebo, while daily
prednisolone was reduced by 2.5 mg every
3 weeks [13]. Results showed for the first time
significant prednisolone reduction of 36% with
active treatment (range 2.5–10 mg, mean 3.75)
vs. a decrease of only 7% (2.5–5 mg, mean
Adv Ther
0.91 mg) in the placebo group. These results
suggested a prednisolone equivalent potency of
1,8-cineole 600 mg of around 2.8 mg that was
well tolerated following steroid reduction. In a
first double-blind, placebo-controlled multi-
centre study of patients (n= 247) with well-
controlled asthma (FEV1 82%) on inhaled
medication guidelines, the effects of adjunctive
therapy with 1,8-cineole (3 9200 mg/day) on
improvement of lung function and Asthma
Quality of Life Questionnaire (AQLQ) were
studied for 6 months [14]. FEV1 increased sig-
nificantly in the cineole group (310 ml) com-
pared to the placebo group (200 ml), and also
some scores of nightly asthma and AQLQ
improved significantly. Caution is advised in
asthmatics with severe perfume incompatibility
since 1,8-cineole is exhaled.
A randomized study in acute bronchitis (n=
242) with 1,8-cineole over 10 days showed sig-
nificant improvements after 4 days of the
bronchitis severity-sum score compared to pla-
cebo [15]. Concomitant therapy with 1,8-cine-
ole (two capsules of 100 mg three times daily)
was also studied in a placebo-controlled study
(n= 242) in COPD (Global Initiative for Chronic
Obstructive Lung Disease (GOLD) II–III) with a
primary outcome of reduction of exacerbations,
and a secondary outcome of changes in lung
function, respiratory symptoms and quality of
life scores during 6 months [16]. Basic medica-
tion consisted of LABA, inhaled corticosteroids
(ICS), anticholinergics and theophylline. All
patients were current smokers or ex-smokers
with at least 10 pack-years. In the group treated
with 1,8-cineole, the number of exacerbations
was significantly (p\0.036) reduced by 38.5%,
as were the severity and duration, FEV1
increased by 78 ml in the range of clinical sig-
nificance and the improvement in SGRQ scores
almost reached significance (p= 0.063). Results
of this first controlled study in COPD suggest
new evidence of the superior therapeutic effi-
cacy of adjunctive therapy with 1,8-cineole to
control COPD exacerbations compared to
combined inhaled therapies with LABA ?ICS
alone.
According to the German Guideline for
COPD [17], 1,8-cineole is recommended in
addition to other mucolytics for its expectorant
activity in dyscrinemic mucus. The guideline
also recommends that substances with anti-in-
flammatory and antioxidant effects can be used
to reduce exacerbations in patients with COPD
and frequent exacerbations and points out that
1,8-cineole has been shown to significantly
reduce exacerbations in patients with COPD
and frequent exacerbations.
ANTI-INFLAMMATORY PROFILE
AND MODE OF ACTION OF 1,8-
CINEOLE
Inflammation is well known as a protective
response to airway injury due to infections and
various inhaled agents and to induce airway
repair by the activation of many pathways, with
the release of multiple inflammatory mediators
that may often be excessive to induce chronic
airway inflammation [18] characteristic of
COPD, asthma and sinusitis. The acute and
often chronic persisting clinical symptoms are
airway hypersecretion and breathing symptoms
that are caused by various mediators, such as
matrix metalloproteinases (MMP-9), vascular
cell adhesion molecules (VCAM-1), cyclooxy-
genase-2 (COX-2), cytosolic phospholipase A
2
(cPLA
2
) and LPS [19]. Various pro-inflammatory
stimuli such as reactive oxygen species (ROS)
from cigarette smoke [20], airway infections and
inflammatory processes are linked with
increased release of cytokines/chemokines (tu-
mour necrosis factor alpha (TNFa), interleukin
(IL)-1b, IL-6, IL-8). These cytokines, as clinical
markers of increased mucus production, exac-
erbations and steroid resistance, induce NF-jB
[21], which is also produced by activation of NF-
jB in response to oxidative stress [22]. These
processes promote induction of airway hyper-
responsiveness and the expression of inflam-
matory genes with relevance in airway diseases.
Beyond these interactions, overprotection
against ROS by cytokine-induced excessive
stimulation or mitochondrial activation and of
the nicotinamide adenine dinucleotide phos-
phate (NADPH oxidase) system in phagocytes is
important for bacterial killing. In this regard, it
is of interest that current guidelines for inhaled
Adv Ther
therapies do not directly control ROS
production.
Original articles on natural products and
reviews on plant species of different herbs con-
taining the monoterpene 1,8-cineole besides
other terpenes report on the anti-inflammatory
and antioxidant activities in various models
[23–25]. Pro-inflammatory cytokines, such as
TNFa, IL-1b, IL-6, IL-8, and COX-2, are known
to be expressed following the dissociation of the
inhibitory protein kappa-light-chain-enhancer
of activated B cells (Ijba) from the NF-jB sub-
units p65 and its translocation from the cyto-
plasm to the nucleus, which is controlled by
various essential oils and their major com-
pounds as promising agents for the treatment of
chronic inflammation [26,27]. The central,
anti-inflammatory mechanism of action of 1,8-
cineole and potentially various other terpenes is
the induction of Ijbaand the prevention of NF-
jB translocation with the consequent control of
pro-inflammatory mediator production [28]. In
addition, in an animal model of LPS-induced
pulmonary inflammation, 1,8-cineole increased
the anti-inflammatory cytokine IL-10 in lung
tissues besides inhibiting TNFa,IL-1band
reducing expression of NF-kB’s subunit p65
[29]. Therefore, preventing NF-jB nuclear
translocation is recommended as the potential
therapeutic target of the antioxidant and anti-
inflammatory monoterpene 1,8-cineole. There
is further evidence that 1,8-cineole also acts as
an analgesic and anti-inflammatory agent by
stimulating the thermosensitive, cool tempera-
ture-detecting transient receptor (TRP) cation
channels (TRPM8) and by inhibiting the human
transient receptor potential cation channel,
subfamily A, member 1 (TRPA1), a known sen-
sor of noxious cold [30].
The anti-inflammatory activity of 1,8-ci-
neole was studied in various preclinical stud-
ies using in vitro and ex vivo models from
normal human subjects and in patients with
asthma and in animal models. We reported
for the first time in healthy subjects and in
patients with asthma the inhibition of
arachidonic metabolism of leukotriene B
4
(LTB
4
) and prostaglandin E
2
(PGE
2
)ofexvivo
cultured monocytes as the first hint of the
anti-inflammatory mode of action of 1,8-
cineole (Soledum
Ò
forte capsules) taken orally
for 4 days, with a regression 4 days after
completion of therapy [31]. These results also
showed for the first time a relevant systemic
anti-inflammatory effect of 1,8-cineole after
oral ingestion of 3 9200 mg/day of Soledum
Ò
forte capsules for 4 days. Early in vitro studies
further reported that 1,8-cineole decreased
(by more than 60%) the production of TNFa,
IL-1b, IL-6 and IL-8 in monocytes [32]andof
TNFa,IL-1b, IL-4 and IL-5 in lymphocytes
[32] from healthy human donors and controls
Th2-type inflammation and Th1/Th2 balance,
which is now controlled downstream in
eosinophilic asthma by IL-5 inhibitors and
receptor antagonists [33]. In these studies,
1,8-cineoleshowedforthefirsttimeasteroid-
like inhibitory effect on stimulated cells
in vitro at the relevant concentration of
10
-5
M(1.5lg/ml)equivalenttotheplasma
level after taking 3 9200 mg of 1,8-cineole
for 14 days [34] [Pidgeon AW. Expert report
on the pharmacokinetics (phase I) of cineole.
1993 (not published)]. This should be taken
into account regarding several animal studies
using much higher concentrations in relation
to body weight. Furthermore, a previous
study evaluated that around 20% of orally
taken 1,8-cineole reaches the peripheral air-
ways and is then exhaled [35]. Besides the
known systemic anti-inflammatory effects in
the blood as a volatile organic compound,
1,8-cineole also reaches the peripheral lung,
which is not possible by currently available
inhaled therapies for asthma and COPD.
When 1,8-cineole is exhaled it also reaches
the paranasal sinuses, which can benefit only
to a limited extent from low blood circulation
of orally administered medications. In a
recent study on a house dust mite (HDM)-
stimulated in vitro model of bronchial
epithelial cells and an HDM-induced murine
asthma model of inhaled 1,8-cineole, Der-
matophagoides pteronyssinus stimulated IL-8,
IL-6, granulocyte macrophage-colony stimu-
lating factor (GM-CSF) and induced airway
hyper-responsiveness (AHR). In this approach,
the numbers of eosinophils in bronchoalveo-
lar lavage fluid (BAL) and of IL-4, IL-13 and
IL-17A were significantly reduced by 1,8-
Adv Ther
cineole [36]. A recent study that investigated
BAL cytokine profiles in healthy subjects
compared to those in controlled and uncon-
trolled asthma showed increased production
of various cytokines (IL-1b, IL-5, IL-6, IL-8
etc.) and of eosinophils and granulocytes in
patients with asthma as compared to patients
without asthma, whereas non-controlled
asthma was distinguished from controlled
asthma only by neutrophil percentage and IL-
8 levels, which correlated with FEV1 [37]. In
eosinophils, high asthma levels of IL-5, IL-13,
IL-16 etc. were higher in the presence of the
same neutrophil percentage, IL-8 and of
FEV1, indicating the role of neutrophils and
IL-8 in uncontrolled asthma with inverse
correlation to lung function [38]. In smokers
with COPD and preserved spirometry (post-
bronchodilator FEV1/forced vital capacity
(FVC) [0.70), systemic inflammatory markers
of IL-6-induced C-reactive protein (CRP) were
associated with a greater number of exacer-
bations and increased symptom burden
(CAT), while increased TNFacorrelated with
an elevated CAT score and CRP and were
negatively correlated with 6-min walking
distance (6MWD) [39]. These data underline
againtheimportantcorrelation,eveninearly
stages COPD, of TNFaand IL-6 (CRP), as
markers of systemic inflammation, for the
progressive symptomatic burden of the
COPD.
In this regard a recently published in vitro
study of cultured human monocytes from nor-
mal, non-smoking subjects showed, at relevant
systemic concentrations of 1,8-cineole
(0.15–1.5 lM), dose-dependent inhibition of IL6
[IL1b[IL-8 CTNFa, with complete inhibition
at therapeutic concentration (1.5 lM) and par-
tial inhibition (20–40%) of IL-1band IL-6 at the
exhaled concentration (0.3 lM) [40]. These data
showed for the first time dose-dependent anti-
inflammatory activities of 1,8-cineole at clini-
cally relevant systemic and also exhaled con-
centrations, since in LPS-stimulated cultured
human monocytes 1,8-cineole demonstrated
the strongest inhibitory effect of 100% on IL-6
at the lowest and almost half the plasma con-
centration (0.6 lM) [40].
A new study reports the importance of
epithelial IL-6 trans-signalling, in the absence of
systemic inflammation, as a new asthma phe-
notype with frequent exacerbations, blood
eosinophilia and increased airway inflamma-
tion with infiltration of T cells and macro-
phages [41].
In summary, this current knowledge repor-
ted 1,8-cineole as a Th1/Th2 cytokine
immunomodulator by its anti-inflammatory
and antioxidant activities to control systemic
inflammation, disease progression, the rate of
exacerbations, steroid resistance and potentially
protective effects against increasing develop-
ment of lung emphysema in inflammatory air-
way diseases. So far, the current state of
knowledge suggests that not only as a mucoly-
tic/secretolytic drug but also by its multifunc-
tional mechanisms 1,8-cineole controls the
cause of mucus production with a peripheral
and systemic availability as compared to
inhaled medications, suggesting the adjunctive
therapy with 1,8-cineole for COPD, asthma and
sinusitis [42] (Fig. 1).
Fig. 1 Various inhalable pollutants as well as viruses and
bacteria induce or intensify pre-existing airway inflamma-
tion. The result is the release of oxygen radicals and
inflammatory mediators, which cause bronchitis with
hypersecretion and acute respiratory distress, depending
on the type of inflammation and genetic determinism. As a
result of the at least bifunctional anti-inflammatory and
antioxidant efficacy profile of 1,8-cineole, this is not only a
symptomatic but also a causative therapy for the treatment
of bronchial complaints. Through this approach, mucus
hypersecretion and recurrent exacerbations are directly
controlled with the aim to reduce the progression of
chronic respiratory diseases
Adv Ther
ANTIOXIDANT ACTIVITY OF 1,8-
CINEOLE AND CONTROL
OF REDOX BALANCE
FOR ADJUNCTIVE THERAPY
IN COPD AND ASTHMA
Oxidative stress and oxidant/antioxidant, pro-
tease/antiprotease imbalance have a major
impact on the severity of symptoms and disease
progression [43]. Oxidative stress is caused by
various ROS, in particular by O
2
-
from cigarette
smoke or by the degree of pulmonary and sys-
temic inflammation responses as produced by
macrophages and neutrophils [44]. O
2
-
is fur-
ther metabolized by superoxide dismutases
(SOD) to H
2
O
2
, with a further breakdown by
catalases [45]. Since H
2
O
2
is also inhaled with
cigarette smoke and is increased when exhaled,
control of H
2
O
2
would be desirable in COPD
[46], which promotes inflammatory airway
responses by the initiation of cytokine produc-
tion. Furthermore, a controlled clinical study
(n= 182) reported decreased levels of ascorbic
acid in smokers and a considerable recovery by
25% after 4 weeks of smoking cessation [47]. A
completed European survey (n= 680) followed
the effect of dietary antioxidants for 10 years on
lung function according to documented food
and vitamin intake and smoking status, and
reports improvements in lung function decline
(FEV1 -3.7 ml/year; FVC -4.5 ml/year), par-
ticularly in ex-smokers [48]. Since current stan-
dard guideline medications of LABA, ICS and of
LAMA only have at most very limited antioxi-
dant effects, it would be of interest to explore
the potential antioxidant activity of the
monoterpene 1,8-cineole for further potential
co-medication.
Recent in vitro studies on the antioxidant
activity of essential oils reported scavenging
activity against ROS [49], ROS effects on
antioxidant enzymes (catalases, SOD, glu-
tathione reductase (GR), heme oxygenase 1
(HO1), glutathione peroxidase (GPx)) induced
by H
2
O
2
[50], nitrogen oxide (NO) and
myeloperoxidase (MPO) production by H
2
O
2
-
stimulated neutrophils [51]. One publication
showed for the first time the antioxidant profile
of 1,8-cineole, at relevant plasma
concentrations (B1.5 lg/ml; 10
-5
M) in foetal
calf serum (FCS)-stimulated normal human
monocytes in vitro, with significant inhibition
of O
2
-
(10
-5
M: -53%), SOD (concentration
independent: -28%) and of H
2
O
2
(10
-10
M:
-48%) [52] (Fig. 2). These data showed for the
first time control of O
2
-
production without
complete inhibition, by virtue of necessary
antibacterial activity with only partial control
of SOD to allow the controlled metabolism of
O
2
-
into pro-oxidant and pro-inflammatory
H
2
O
2
, which is also directly controlled at very
low concentrations of systemic and exhaled
concentrations of 1,8-cineole.
LPS-stimulated 8-isoprostane (8-Isop) as a
marker of total antioxidant activity was dose-
dependently (10
-6
M: -42%; 10
-5
M: -84%)
inhibited [52]. This is of interest since exhaled
8-Isop became known as an in vivo biomarker of
lung oxidative stress in patients with COPD and
healthy smokers [53]. On the basis of these
results, the most promising approach in
repeatedly exacerbated COPD or steroid-de-
pendent asthma is reversal of corticosteroid
resistance through increasing histone deacety-
lase 2 (HDAC2) activity, where 1,8-cineole
should be recognized as a more effective
Fig. 2 Cigarette smoke is rich in oxygen radicals that
induce bronchial hypersecretion and, among other activ-
ities, steroid resistance. Oxygen radicals (O
2
-
) are
degraded via the activity of superoxide dismutases (SOD)
to hydrogen peroxide (H
2
O
2
), which induces bronchial
inflammation. In vitro studies of foetal calf serum-
stimulated human monocytes showed modulating antiox-
idant effects of therapeutically relevant concentrations of
1,8-cineole with approximately 50% inhibition of O
2
-
and H
2
O
2
and a partial inhibition in this approach of
SOD [52]
Adv Ther
antioxidant with additional anti-inflammatory
activities [54].
O
2
-
radicals are inhaled and released from
activated inflammatory cells during exacerba-
tions as the most putative risk factors to stim-
ulate bronchial hypersecretion and
inflammatory airway responses in COPD and
asthma, in addition to their pro-carcinogenic
activities. In moderate COPD (GOLD II, n= 23)
the antioxidant capacity of the natural thiol-
containing antioxidants GPx was reduced and
in severe COPD (GOLD III, n= 56) the antioxi-
dant lipid peroxidation product malondialde-
hyde (MDA) was significantly higher than in
moderate COPD [55]. These results suggested an
association between oxidative stress and
obstructive lung impairment as a measure of
COPD severity. An earlier controlled study in
mice exposed to cigarette smoke (CS) for 5 days
reported for the first time that CS-induced acute
lung inflammation of increased metallopro-
tease 12, TNFaand NF-jB activation was
reduced by non-thiol compound supplementa-
tion with the vitamins ascorbic acid and a-to-
copherol [56]. In this regard, recent results from
a mouse model of intermittent hypoxia, rele-
vant for severe COPD, showed increased ROS
production and elastase activity that could be
controlled by antioxidative L-glutathione and
the TNFaantagonist infliximab [57]. In various
in vitro and animal studies with essential oils
1,8-cineole was reported as the main antioxi-
dant compound [58,59]. Short-term exposure
to inhaled eucalyptol (3 mg, 10 mg for 5 days)
in a mouse model decreased oxidative stress by
the inhibition of ROS, SOD, catalase and MDA,
and showed anti-inflammatory efficacy by the
inhibition of NF-kB’s p65 subunit and of IL-1b,
IL-6 and of TNFaat the highest concentration of
10 mg/day, suggesting relevant antioxidative
and anti-inflammatory activities [60]. In this
report, 1,8-cineole promoted lung repair at
higher doses with de novo formation of alveoli
as compared to the control group. In this study,
lung regeneration by 1,8-cineole resulted in the
upregulation of elastin, tissue inhibitor of
matrix metalloproteinase (TIMP-1) and antiox-
idant, anti-inflammatory protective effects by
the reduction of anti-inflammatory (MPO,
TNFa, IL-1b, IL-6 etc.) and redox marker levels.
Using a similar design, a further study with
inhaled concentrations of eucalyptus oil
(10-300 mg/kg) also reports prevention of lung
injury [61]. A new review is focusing on the
importance of controlling various disease
mechanisms of oxidative stress in chronic res-
piratory diseases (CRDs) including asthma,
COPD, respiratory infections, and also lung
cancer, which are not sufficiently controlled by
available anti-inflammatory therapies, such as
ICS, LABAs, NF-jB inhibitors, mitogen-activated
protein kinase p38 (MAPK p38) inhibitors and
PDE-IV inhibitors with no effect on disease
progression in COPD [62]. Although ICS are the
basic medications for control of airway inflam-
mation in asthma, glucocorticosteroids were
not effective in preventing oxidative stress-me-
diated airway inflammation by steroid-related
interference with anti-inflammatory gene
expression and antioxidant enzymes [63].
To summarize, current knowledge on the
role of a balanced ratio of oxidants and
antioxidants, especially in the pathophysiology
of COPD and asthma, has suggested the
importance of effective antioxidant therapy in
inflammatory airway diseases. Since standard
therapies with LABA ?ICS seem not to provide
any antioxidant effects, compensation with
adjunctive therapy with 1,8-cineole is an option
for achieving relevant antioxidant effects of
standard inhaled therapies for the lungs.
ANTIMICROBIAL AND ANTIVIRAL
EFFECTS OF 1,8-CINEOLE
AND ESSENTIAL OILS
There is increasing knowledge on the role of the
respiratory microbiome in lower and upper air-
way disease, which may have an impact on
disease severity, in particular with the fre-
quency of exacerbations and the underlying
disease phenotype [64]. Changes to the airway
microbiome by external viral and bacterial
infections could potentially induce microbial
dysbiosis with clinical relevance of interactions
with inflammatory airway-induced exacerba-
tions [65]. In this regard long-term treatment in
controlled clinical studies with the antibiotic
and anti-inflammatory-acting azithromycin
Adv Ther
showed improvement of exacerbations and
disease severity in severe COPD [66] by the
downregulation of various antigen-regulating
genes and of inflammatory T cell responses in
various inflammatory pathways [67]. Also Glo-
bal Initiative for Asthma (GINA) guidelines
recommend the use of the antibiotic and anti-
inflammatory azithromycin as co-medication
(500 mg three times weekly) in Th1-type
inflammation for neutrophilic, uncontrolled
asthma, with, however, no significant effect on
total bacterial load [68]. 1,8-Cineole was also
reported to protect against influenza viral
infections in mice and virus-induced pul-
monary cytokine production of IL-1b, IL-6 and
TNFaby the control of NF-kB p65 expression
[28] and the induction of the antiviral tran-
scription factor inteferon regulatory factor 3
(IFR3) [12].
New research directly focusing on the
antimicrobial activity of various eucalyptus oils
with the main component of 1,8-cineole,
ranging from 66.93% to 97.3%, inhibited or
killed in vitro the majority of microorganisms
[69]. Furthermore, both Eucalyptus globulus
essential oil and 1,8-cineole prevented biofilm
formation by methicillin-resistant Staphylococ-
cus aureus (MRSA) and subsequently the
spreading of nosocomial infection. A recent
study reports genetic downregulation of biofilm
induction in chronic rhinosinusitis by 1,8-ci-
neole with inhibition of relevant microbial
pathogens (S. aureus,Escherichia coli,Moraxella
catarrhalis) and pro-inflammatory NF-jB target
genes at relevant concentrations [70]. This may
be of further relevance, since in another study
the microbiome profile was assessed by using
sequencing of the 16S rRNA gene for the follow-
up of hospitalized patients with acute exacer-
bated COPD (AECOPD) who did not survive
with higher Staphylococcus levels [71]. A former
study of the pharmacokinetics of inhaled 1,8-
cineole in humans showed peak plasma con-
centrations after 18 min, with a biphasic mean
distribution of 6.7 min and an elimination half-
life of 104.6 min [72]. Besides the oral route,
application of 1,8-cineole by vapour inhalation
has been suggested for exacerbated purulent
and non-purulent bronchitis, asthma and
COPD owing to its long history of usage and
good safety record [73]. In a recent compre-
hensive in vitro study, the monoterpene 1,8-
cineole was demonstrated as the major com-
pound (up to 70.4%) of different eucalyptus oils
that were investigated for the minimal inhibi-
tion concentration (MIC) and the minimum
bactericidal concentration (MBC) to kill 99.4%
of bacterials after incubation for 18-24 h [74].
In this study, eucalyptus species with a content
of 1,8-cineole of 42-70.4% showed antibacte-
rial activities of 8.1-27.4% against Haemophilus
influenzae,Klebsiella pneumoniae,Pseudomonas
aeruginosa,S. aureus,Streptococcus agalactiae,
Streptococcus pneumoniae and Streptococcus pyo-
genes compared to various antibiotics
(19.9-37.5%). Also antifungal and antiviral
activities were reported for these eucalyptus
species, however with generally only a minimal
chance for the development of resistance com-
pared to antibiotics. Such data would be of great
interest, since 16S ribosomal RNA gene
sequencing and host gene expression analyses
by quantitative real-time PCR actually showed
associations between host gene expression and
microbiota lung profiles by correlation of the
severity of COPD (GOLD III–IV) and potentially
the course of the disease. In vitro studies on the
sensitivity of microbes to various species of
eucalyptus oils with a major content of 1,8-ci-
neole were reviewed [75]. In summary, current
data suggest a clinical relevant antiviral and
antibacterial activity of 1,8-cineole.
SUMMARY: AT LEAST
BIFUNCTIONAL ACTIVITIES OF 1,8-
CINEOLE TO IMPROVE COPD
AND ASTHMA UNDER GUIDELINE
THERAPIES
In a previous report 1,8-cineole was shown for
the first time to induce additively the anti-in-
flammatory efficacy of ICS and of combined
inhaled therapies of LABA ?ICS in vitro at the
approximate airway concentrations of exhaled
1,8-cineole [40]. Additionally, a recent publica-
tion reports for the first time on the antioxidant
effects of 1,8-cineole with a highly superior
suppression of O
2
-
(-53%) at a relevant
Adv Ther
plasma concentration (10
-5
M) as compared to
the strongest effects of budesonide (BUD)
(10
-9
M: -10.5%) and formoterol (F) (10
-10
M:
-10.8%) alone [52]. At increasing concentra-
tions (10
-8
M), weak inhibitory effects of BUD
and F changed into significant small pro-ox-
idative activities with at least no pro-oxidative
or antioxidative effects of therapeutically rele-
vant combinations of BUD ?F. These results
showed that 1,8-cineole has at least two differ-
ent pharmacological actions in the same mole-
cule as a bifunctional drug besides it
bronchodilatory, antimicrobial and other
activities for the treatment of inflammatory
airway diseases.
Th1-type inflammation in high IL-17 phe-
notype very often plays a key role in frequently
exacerbating neutrophilic asthma and COPD
[76], which is also controlled by 1,8-cineole in
addition to its control of Th2-type inflamma-
tion [33]. In this regard, adjunctive pulse ther-
apies with azithromycin (3 9500 mg per week)
[77] and clarithromycin (2 9500 mg per week)
[78] for 1 year are recommended only for these
antibiotics to control exacerbations besides
known side effects (evidence A) by the current
Task Force Report of the GOLD Executive
Summary [4]. For other mucolytic (mucokinet-
ics, mucoregulators) and antioxidant agents
(NAC, carbocysteine), however, as a result of the
partial (IL-6) or missing anti-inflammatory (IL-
1b, IL-8, TNFa) efficacy of NAC, the antioxi-
dant/anti-inflammatory activity of NAC and
carbocysteine seemed to be relevant only in
patients not receiving ICS [79]. Evidence of
vitamin D supplementation was only reported
in patients with COPD and vitamin D defi-
ciency (25-hydroxyvitamin D
3
\25 nmol) [80],
and oxidative stress in severe asthma exacerba-
tions was linked with vitamin D deficiency,
increased release of ROS, TNFaNF-jB expression
[81] and downregulated expression of gluco-
corticoid receptors by H
2
O
2
. For this reason,
owing to at least a bifunctional anti-inflamma-
tory/antioxidant mode of action, the monoter-
pene 1,8-cineole seems to be a more promising
adjunctive therapy for COPD and asthma,
including the asthma–COPD overlap type
(ACO), though clinical studies are still rare.
Previous randomised controlled trials on the
exacerbation rates in COPD with therapies of
LABA ?ICS compared to LABA ?ICS ?1,8-ci-
neole have shown an add-on effect of 1,8-cine-
ole [14], with a stronger reduction of
exacerbations compared to LABA ?ICS (Fig. 3).
In the cineole study, patients with COPD were
enrolled with 80% on LABA and 23% on ICS,
suggesting a relevant ICS-like effect of the
multifunctional 1,8-cineole in real life that
might have been even greater in patients with
COPD on currently recommended standard
medications of LAMA ?LABA or LAMA ?
LABA ?ICS. Following antagonism of mus-
carinic M
1
/M
3
receptors by tiotropium, inhibi-
tion of NF-jB and IL-8 in LPS-stimulated
bronchial epithelial cells and airway fibroblasts
[82] was shown in addition to the published
inhibition of many other cytokines. In a guinea
pig model of allergic asthma, combined treat-
ment with a nebulizer concentration of tio-
tropium (0.01 mM) and ciclesonide (0.01 mg/
kg) inhibited eosinophilic airway inflammation
and remodelling, which was not shown for the
Fig. 3 Previous randomized trials in COPD found a
decrease in exacerbation frequency for LABA ?ICS in
the range of 24%, regardless of the amount of ICS used
[85–88], with only a slight difference to ICS alone (20%)
[89]. Studies with monotherapy of a LAMA [90,91]or
PDE-IV inhibitor [92] showed comparable reductions
(14-18%) of exacerbations such as ICS alone. In recent
studies with LAMA ?LABA, however, there a nearly
twofold decrease in exacerbations in the range of 50% has
been detected [93,94]. For the first time, the effect of
adjunctive therapy with the monoterpene 1,8-cineole
showed a 38% decrease in exacerbations
Adv Ther
two substances when administered alone [83].
1,8-Cineole also showed an airway relaxant
effect in a guinea pig model at relevant con-
centrations (greater than 6.5 910
-6
M) with a
decreased effect on tracheal hyper-responsive-
ness to KCl and carbachol, whereas the effect of
acetylcholine (10
-4
M) was only partially con-
trolled at higher concentrations of 1,8-cineole
(6.5 910
-3
M), suggesting an additional action
on electromechanical coupling [84]. The clini-
cal effect of LAMA, such as that of M
1
/M
3
antagonism by tiotropium, may be improved by
the at least bifunctional anti-inflammatory and
antioxidant activity of the mucolytic agent 1,8-
cineole. Since 1,8-cineole primarily controls IL-
1band TNFa, adjunctive therapy with 1,8-ci-
neole in inflammatory airway diseases is rec-
ommended for the protection of virus-induced
M
2
receptor dysfunction and to improve the
effects of LAMA alone or in combinations with
LABA and/or ICS. With respect to the new
guideline recommendation for COPD, prelimi-
nary in vitro results now show for the first time
that 1,8-cineole also controls the pro-inflam-
matory effects of acetylcholine (ACh), thus
improving the anti-inflammatory effects of iso-
lated M
1
/M
3
receptor antagonism of LAMAs
(Fig. 4).
These preliminary results suggest that rele-
vant respiratory and plasma concentrations of
1,8-cineole, at least in the present experimental
design, could mediate a comparable or higher
anti-inflammatory activity than tiotropium
alone and also additively intensifies its anti-in-
flammatory effects. For this reason, adjunctive
therapy with 1,8-cineole is also suggested with
LAMA therapy in the early stages of symp-
tomatic COPD (GOLD I–IIB) to control exacer-
bation and also, potentially, the progression of
cigarette smoke-induced neutrophilic and eosi-
nophilic airway inflammation.
LESSONS FOR CLINICIANS
Inflammatory processes, particularly in COPD,
are characterized by only partial therapy
responses to ICS, depending on the type of
inflammation, such as the COPD–bronchitis
type with exposure to CS, inhaled ROS and/or
by increased production of exacerbation acti-
vated airway cells or the degree and mixture
with neutrophilic/eosinophilic Th1/Th2-type
inflammation in asthma and ACO. As previ-
ously shown [40,52] in vitro, anti-inflamma-
tory and antioxidant effects increased additively
by co-incubation of 1,8-cineole ?ICS or 1,8-
cineole ?(ICS ?LABA), whereas BUD ?Fat
least did not show any pro- or antioxidant
activity as shown for O
2
-
. This would suggest a
therapeutic value for 1,8-cineole as adjunctive
therapy for partial ICS responders by its control
of Th1-type inflammation in steroid-resistent
asthma, independently of eosinophilia or Th2-
type inflammation, and of the COPD–bronchi-
tis type, with and without sinusitis, by its
bifunctional antioxidant and anti-inflamma-
tory activity, or in patients with asthma, COPD
and ACO with frequent exacerbations under
Fig. 4 In an in vitro model (10
5
/ml, 2 Expt., n=6)of
human monocytes from healthy volunteers (expressing
M
1
–M
5
receptors), the effects of respiratory-relevant
concentrations (2 910
-6
M) and a relevant plasma
concentration (4 910
-6
M) of 1,8-cineole (C), tiotro-
pium 15 pg/ml (TIO) alone and of TIO ?C after
incubation for 20 h were investigated for IL-8 in the
presence of LPS (10 lg/ml) (Sigma-Aldrich, Germany).
Stimulated IL-8 production was inhibited (p\0.0001
compared to the LPS control) in a dose-dependent
manner, even comparable to tiotropium (TIO) (15 pg/
ml) at a small exhaled and therefore respiratory-relevant
concentration of C (2 910
-6
M). This inhibitory effect
of TIO on IL-8 production increased significantly after co-
incubation with the investigated breath-relevant concen-
tration of C, and further dose-dependently, at an increas-
ing, small systemically relevant concentration
(4 910
-6
M)
Adv Ther
standard triple therapy. In this regard, it may be
of interest that the anti-inflammatory in vitro
effect of LAMAs increased in the presence of
anti-inflammatory agents, such as 1,8-cineole or
ICS, possibly in part by protection against
infection or inflammation-induced M
2
receptor
dysfunction or by improvement of the effects of
M
1
/M
3
receptor inhibition, though the precise
mechanism of action seems so far not to be
understood. For this reason, a non-steroidal
anti-inflammatory substance, such as 1,8-cine-
ole, could be recommended in the early COPD
stages of groups without (A) or with (B) clinical
symptoms in the known typical range of indi-
cation for 1,8-cineole and as adjunctive therapy
to LAMA for symptomatic early COPD.
CONCLUSIONS
Independently of mono- or adjunctive therapy
with 1,8-cineole, long-term therapy, because of
its antiviral, antibacterial, antioxidant and anti-
inflammatory activity, is to be recommended
besides its effects to control systemic and
peripheral lung inflammation, an area that is
not generally reachable for standard inhalation
therapies.
ACKNOWLEDGEMENTS
We acknowledge the helpful cooperation of Dr
M. Ploch, Cassella-med Ltd, Cologne, Germany
and Dr H. Greve, Du
¨sseldorf, Germany.
Funding. The study, rapid service fee and
the open access fee was funded by Cassella-med
Ltd, Cologne, Germany.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Authorship Contributions. LJ (medical stu-
dent) and UJ carried out the literature search
and the interpretation of cited data. UJ
developed the design and conception of the
study. UJ, LJ and HW were involved in drafting
and revising the manuscript.
Disclosures. Uwe Juergens was a member of
the advisory board at Cassella-med Inc. Lisa Joy
Juergens and Heinrich Worth have nothing to
disclose.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not contain any studies with human
participants or animals performed by any of the
authors.
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
Open Access. This article is licensed under a
Creative Commons Attribution-NonCommer-
cial 4.0 International License, which permits
any non-commercial use, sharing, adaptation,
distribution and reproduction in any medium
or format, as long as you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons licence, and
indicate if changes were made. The images or
other third party material in this article are
included in the article’s Creative Commons
licence, unless indicated otherwise in a credit
line to the material. If material is not included
in the article’s Creative Commons licence and
your intended use is not permitted by statutory
regulation or exceeds the permitted use, you
will need to obtain permission directly from the
copyright holder.To view a copy of this licence,
visit http://creativecommons.org/licenses/by-
nc/4.0/.
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